U.S. Pat. No. 5,948,792 discloses fluorine-containing 1,4-disubstituted piperidine derivatives. These compounds are muscarinic M3 receptor antagonists useful for the treatment or prophylaxis of respiratory diseases such as chronic obstructive pulmonary diseases, chronic bronchitis, asthma and rhinitis; digestive diseases such as irritable bowel syndrome, convulsive colitis, diverticulitis and pain accompanying contraction of smooth muscles of the digestive system; urinary disorders like urinary incontinence and frequency in neurogenic pollakiuria, neurogenic bladder, nocturnal enuresis, unstable bladder, cystospasm and chronic cystisis; and motion sickness.
(2R)-N-[1-(6-aminopyridin-2-ylmethyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide (A) is a potent and selective M3 receptor antagonist; its preparation from (2R)-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxyphenylacetic acid and 2-amino-6-[(4-aminopiperidin-1-yl)methyl]pyridine is described in U.S. Pat. No. 5,948,792.
The synthesis of 2-amino-6-[(4-aminopiperidin-1-yl)methyl]pyridine (I) described in U.S. Pat. No. 5,948,792 is summarized below: 
The previous synthetic routes to compound (I) involved a cryogenic reaction, large reaction volumes, reactions under high pressure, the use of relatively expensive reagents and provided compound (I) containing problematic impurities. Thus there remains a need for an improved synthetic route to compound (I) that is amenable to large scale production without having to resort to relatively inaccessible reagents, extreme temperatures and pressures or toxic metals.
The present invention provides an improved process for the preparation of 2-amino-6-[(4-aminopiperidin-1-yl)methyl]pyridine acid addition salts using commercially available starting materials, intermediates in the process, as well as an improved process for the preparation of the M3 antagonistic compound of formula (A).
In one aspect the present invention provides a process for the preparation of 2-amino-6-[(4-aminopiperidin-1-yl)methyl]pyridine of formula (I) acid addition salt: 
which comprises the steps of:
a) treating 2-(trimethylacetylamino)-6-[(4-protected aminopiperidin-1-yl)methyl]pyridine with a mineral acid or a strong organic acid; and
b) isolating the acid addition salt of 2-amino-6-[(4-aminopiperidin-1-yl)methyl]pyridine.
In another aspect, the process further comprises the step of providing 2-(trimethylacetylamino)-6-[(4-protected aminopiperidin-1-yl)methyl]pyridine by reacting 2-(trimethylacetylamino)-6-formylpyridine with 4-protected aminopiperidine or an acid addition salt thereof, in the presence of a reducing agent.
In a further aspect, the process comprises the additional step of providing 2-(trimethylacetylamino)-6-formylpyridine by treating 2-(trimethylacetylamino)-6-bromopyridine with a metallating agent followed by a formamide of the formula HC(O)NR1R2 wherein R1 and R2 are independently selected from C1-5alkyl and phenyl.
In a further aspect the process comprises the additional step of providing 2-(trimethylacetylamino)-6-bromopyridine by reaction 2-amino-6-bromopyridine with an acylating agent derived from trimethylacetic acid.
The above reactions are depicted in the following Scheme 1 starting from 2-amino-6-bromopyridine: 
In the first step, commercially available 2-amino-6-bromopyridine is treated with an acylating agent derived from trimethylacetic acid such as trimethylacetyl chloride or trimethylacetic anhydride, preferably trimethylacetyl chloride, in the presence of a base. Suitable base includes tertiary amines such as triethylamine, tributyl amine, diisopropylethylamine, pyridine, picoline, lutidine, collidine, imidazole and the like. The reaction is carried out in an aprotic solvent such as chlorinated hydrocarbons such as dichloromethane, dichloroethane or dichlorobenzene; hydrocarbons such as toluene, xylene, cyclohexane, hexane or heptane; ethers such as methyl t-butyl ether, dibutyl ether, tetrahydrofuran or the glymes; esters such as ethyl acetate, isopropyl acetate or butyl acetate; or other polar aprotic solvents such as acetonitrile, dimethylformamide, N-methylpyrrolidinone or dimethylsulfoxide. Glymes as used herein include ethylene glycol dimethyl ether (dimethoxyethane), diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, and the like. The reaction is conducted at a temperature of between about 0xc2x0 C. to about 50xc2x0 C., preferably from about 20 to about 50xc2x0 C.
In the second step, 2-(trimethylacetylamino)-6-bromopyridine is treated with a metallating agent followed by a formamide of the formula HC(O)NR1R2 wherein R1 and R2 are independently selected from C1-5alkyl and phenyl to provide 2-(trimethylacetyl)-6-formylpyridine. Suitable metallating agent are for example, Grignard reagent such as cyclohexylmagnesium chloride, isopropylmagesium chloride, and the like; alkyllithium such as n-butyllithium; dialkyl magnesium compounds such as dibutylmagnesium or diisopropylmagnesium; or mixtures of an alkyl lithium with a Grignard reagent, a dialkylmagnesium, or a magnesium halide. The preferred metallating agent is isopropylmagnesium chloride. The reaction is carried out in an organic solvent such as hydrocarbons such as toluene, xylene, cyclohexane, hexane or heptane; ethers such as tetrahydrofuran, diethyl ether, dibutyl ether, or the glymes. The reaction is carried out at temperature of between about 0-25xc2x0 C., preferably from about 0 to about 20xc2x0 C., and optionally in the presence of a complexing agent such as tetramethyl ethylenediamine. The metallation reaction is typically complete within about 24 hours. The metallated species is then converted to the aldehyde using a formamide such as dimethylformamide or N-methyl N-phenylformamide.
In the third step, reductive amination of 2-(trimethylacetyl)-6-formylpyridine is accomplished using a 4-protected aminopiperidine, preferably as a carboxylic acid salt such as the acetate or formate salt, in the presence of a reducing agent such as sodium triacetoxyborohydride, sodium borohydride, sodium cyanoborohydride, borane and its adducts, formic acid, or catalytic hydrogenation. The reaction is carried out in a solvent such as dimethylformamide, acetonitrile, ethers such as tetrahydrofuran, dibutyl ether, tetrahydropyran or the glymes; esters such as ethyl acetate, methyl acetate, isopropyl acetate or butyl acetate; alcohols such as methanol, ethanol or isopropanol, propanol, butanol or methoxyethanol; or other polar aprotic solvents such as N-methylpyrrolidinone or dimethylsulfoxide. The reaction is carried out at a temperature of between about xe2x88x9240xc2x0 C. to about room temperature, and conveniently may be carried out at ambient temperature. The amino protecting group for 4-aminopiperidine may be a conventional amino protecting group, and preferably one that can be easily removed concurrently with the trimethylacetyl group, such as lower alkanoyl, for example acetyl, and alkoxycarbonyl, for example t-butoxy-carbonyl. The 4-(protected amino)piperidine is preferably used in the presence of a lower alkanoic acid such as acetic or formic acid bound to the piperidine. In a preferred embodiment, the 4-(protected amino)piperidine is N-(4-piperidinyl)-acetamide acetic acid salt; the reductive amination product, 2-(trimethylacetylamino)-6-[(4-acetylamino)-1-piperidinyl)methyl]pyridine, is a crystalline material which can be easily purified and isolated.
In the fourth step, the amino protecting group and the trimethylacetyl group of 2-(trimethylacetylamino)-6-[(4-protected amino)-1-piperidinyl)methyl]-pyridine are removed. The specific reagent and conditions used will depend on the protecting group. Preferably, the amino protecting group is one that can be removed using the reagent and under conditions suitable for removal of the trimethylacetyl group. Conveniently, the amino group may be protected as the acetamide, which may be deprotected by heating aqueous mineral acid such as HCl, HBr or sulfuric acid in an alcohol such as methanol, ethanol, propanol or isopropanol to reflux. Strong organic acid such as sulfonic acids such as methanesulfonic or toluenesulfonic acid may be used in place of the mineral acid. The amino group may also be protected as the carbamate, in which case, deprotection is performed by treatment with mineral acid such as HCl, HBr or sulfuric acid as well as strong organic acids such as the sulfonic acids ie methanesulfonic acid and toluenesulfonic acid, with or without water, in an alcohol such as methanol, ethanol, propanol or isopropanol as well as any solvent that does not compete significantly with the substrate in the deprotection.
The product of the deprotection step may be purified and isolated using conventional separation techniques such as crystallization or resin chromatography.
In another aspect of the present invention there are provided the following novel compounds: 2-(trimethylacetylamino)-6-bromopyridine; 2-(trimethylacetylamino)-6-formylpyridine; and 2-(trimethylacetylamino)-6-[(4-protected amino-piperidin-1-yl)methyl]pyridine.
In yet another aspect the present invention provides a process for the preparation of the M3 antagonist compound (2R)-N-[1-(6-aminopyridin-2-ylmethyl)-piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide (formula A) or a pharmaceutically acceptable thereof, which comprises the steps of:
a) treating 2-(trimethylacetylamino)-6-[(4-protected aminopiperidin-1-yl)methyl]pyridine with a mineral acid or a strong organic acid;
b) isolating the acid addition salt of 2-amino-6-[(4-aminopiperidin-1-yl)methyl]pyridine;
c) reacting the product of step b) with an acid of the formula (B) 
an acylating agent thereof;
d) optionally converting the product of step c) into a corresponding pharmaceutically acceptable salt.
The first two steps in the above process have been previously described in detail. The coupling of the acid of formula (B) and the amine of formula (I) maybe carried out under conventional amide formation conditions. Thus, the reaction may be carried out in the presence of coupling agents such as a carbodiimide (e.g., 1-ethyl -3-(3-dimethylaminopropyl)carbodiimide) and hydroxybenzotriazole. The acid may also be converted into an acylating equivalent, such as the corresponding acid chloride, and reacted with the amine compound in the presence of a base such as secondary and tertiary amines.
As compound of formula (A) contains basic nitrogen atoms, it may be converted to pharmaceutically acceptable acid addition salts by treatment with an appropriate acid. Suitable acids include inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like. Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.
In another aspect, the process for the preparation of compound of formula (A) further comprises the step of providing 2-(trimethylacetylamino)-6-[(4-protected aminopiperidin-1-yl)methyl]pyridine by reacting 2-(trimethylacetylamino)-6-formylpyridine with 4-protected aminopiperidine or an acid addition salt thereof, in the presence of a reducing agent.
In a further aspect, the process for the preparation of compound of formula (A) comprises the additional step of providing 2-(trimethylacetylamino)-6-formylpyridine by treating 2-(trimethylacetylamino)-6-bromopyridine with a metallating agent followed by a formamide of the formula HC(O)NR1R2 wherein R1 and R2 are independently selected from C1-5 alkyl and phenyl.
In a further aspect the process for the preparation of compound of formula (A) comprises the additional step of providing 2-(trimethylacetylamino)-6-bromopyridine by reacting 2-amino-6-bromopyridine with an acylating agent derived from trimethylacetic acid.
The various additional steps for the preparation of 2-(trimethylacetylamino)-6-bromopyridine have already been described in detail hereinabove.